Human inducible pluripotent stem (iPS) cells are a new valuable source of cells with characteristics similar to those of embryonic stem cells. This new resource of pluripotent cells could indeed circumvent the ethical questions surrounding the destruction of human blastocysts. It is now well established that pluripotent cells can be manipulated to form cells of all 3 germ layers that can be used for disease treatment. Thus, the use of human non-embryonic pluripotent cells is ethically compelling and requires thorough investigation. More importantly, iPS cells could be derived directly from a patient followed by differentiation into progenitor cells and then given back to the patient for the treatment of degenerative diseases without the need for immunosuppression. The long-term goal of our studies is to utilize human iPS cells for the derivation of hematopoietic progenitor cells that can be used to treat human hematopoietic malignancies, immunodeficiencies and for the establishment of transplantation tolerance. Immunity of these cells will be established to determine whether or not they can be transplanted across MHC barriers with/without immunosuppressive regimens. Here, we will apply our knowledge acquired in the mouse to manipulate pluripotent human cells for the derivation of hematopoietic progenitor cells. Our hypothesis is that human pluripotent cells can be manipulated to form hematopoietic cells. Further, we will elucidate the regulatory networks in iPS cell- derived hematopoietic progenitor cells. Additionally, the role of microRNAs in hematopoietic stem cells will be examined. This proposal will be performed between the labs of the PI, an established transplant immunologist and stem cell biologist and the labs of Drs. Xue and Levasseur, independent PIs at the University of Iowa, who are highly trained and experts in stem cell genomics. We believe that these studies between our three labs synergize extremely well and will facilitate the establishment of pluripotent cells as a source of stem cell progenitors. The rationale for these studies is that these newly developed cells might lead to a broader use for stem cells across MHC barriers without the need for severe immunosuppressive agents. This argument is supported by our own lab data indicating poor MHC expression and reduced in vivo immunogenicity by ES-derived hematopoietic progenitor cells.